Purification of 2-ethyl-cis-crotonylurea



United States Patent PURIFICATION OF Z-ETHYL-CIS-CROTONYLUREA Robert J. Langenberg, Zeeland, Micln, assignor to Miles Laboratories, Inc., Elkhart, -Ind., a corporation of Indiana No Drawing. Application Mayx16, 1958 Serial No. 735,712

1 Claim. (Cl. 260-553) This invention relates to 2-ethyl-cis-crotonylurea and more particularly to a new and improved process of purifying the same.

The higher melting isomer of 2-ethylcrotonylurea, 2-ethyl-cis-crotonylurea, has been found to be particularly useful in standard pharmaceutical excipients or dispersants as a hypnotic or sedative for human use. It has been prepared on a commercial scale by refluxing carbromal (2-bromo-2-ethylbutyrylurea) in isopropanol with anhydrous silver oxide. The reaction mixture, while still hot from the refluxing step, is then filtered to remove silver bromide and the filtrate allowed to cool. Subsequently the cold filtrate is centrifuged to separate out and permit recovery of the crude Z-ethyl-cis-crotonylurea. The crude product thus obtained, however, has been found to contain a disproportionately large amount of silver, up to 6000 p.p.m., which it has been found, is extremely difiicult to remove with any degree of satisfactory results even after repeated recrystallizations from fresh boiling isopropanol and treatments with char.

Accordingly, a principal object of the invention is to provide means and method of treating the crude Z-ethylcis-crotonylurea produced by the aforementioned process in order to reduce its silver residue content to a minimum.

Still another object of the invention is to provide a process of treating the crude 2-ethyl-cis-crotonylurea by which its silver residue content can be consistently reduced to a quantity below 5 p.p.m.

Another object is to provide an improved method of manufacturing 2-ethyl-cis-crotonylurea by which a purer form of the higher melting isomer can be produced.

Still another object of the invention is to modify the aforedescribed process of producing the higher melting isomer of Z-ethylcrotonylurea through the reaction of silver oxide and carbromal in refluxing isopropanol so that a product can be obtained having a much lower silver residue content mixed therewith.

A still further object is to provide simple, convenient and efficient, practical means and method of producing the higher melting isomer of 2-ethylcrotonylurea which will be completely free or nearly so of silver mixed therewith.

In keeping with these and other objects of the invention, it has been found that if small amounts of phosphoric acid are added to the refluxing isopropanol in which the crude Z-ethyl-cis-crotonylurea is prepared, the crude product obtained from the dehydrohalogenation of carbromal in the presence of silver oxide, after the filtration and isolation, will consistently contain less than 50 p.p.m. of silver as compared with a previously more usual content approaching 6000 p.p.m.

It has also been found that consistently good results can be obtained if small amounts of phosphoric acid are added to the isopropanol solution from which the crude Z-ethyI-cis-crotonylurea, containing the undesired silver residue, is recrystallized. Thus it has been found that if the crude 2-ethyl-cis-crotonylurea, as obtained by said dehydrohalogenation of carbromal with silver oxide, is

dissolved in boiling isopropanol and the solution treated with a small amount of phosphoric acid (approximately .05'% by total weight of a batch) and the solution treated with char, then after subsequent filtration to remove the char, cooling, and centrifuging to remove-the crystalline solid, an essentially pure higher melting isomer of 'Z-ethylcrotonylurea can be obtained. By this purification treat ment, yields of the higher melting isomer 2-ethylcrotonyl urea have been consistently obtained having a silver residue content of less than 5 p.p.m. Phosphoric acid seemed to be much more applicable in this respect. other acids such -as acetic acid, hydrochloric acid and hydrobromic acid, which did notgive the same consistent yield of pure 2-ethyl-cis-cr'ot'onylurea containingless 5p.-p.m. of silver.

EXAMPLE 1 To illustrate the process, a quantity of the higher melting isomer of Z-ethylcrotonylurea was prepared in the laboratory by refluxing 45 0 grams of carbromal with 225 grams of anhydrous silver oxide in 3600 cc. isopropanol for three hours, accompanied by stirring. The crude 2-ethyl-cis-crotonylurea was extracted by filtration after cooling and found to contain 800 p.p.m. of silver. One hundred forty-four (144) grams of the crude 2-ethyl-ciscrotonylurea thus obtained was dissolved in 3000 cc. of isopropanol and 1 ml. of phosphoric acid was added to the solution. The material was then treated with 2 grams of Norit (which is an activated carbon manufactured by American Norit Company, Jacksonville, Florida) and filtered. One hundred twenty-one (121) grams of pure Z-ethyl-cis-crotonylurea were extracted from the cold fil trate by filtering, which, on examination, was found to contain less than 5 p.p.m. of silver and melting at 188- 189".

EXAMPLE 2 A sample of crude 2-ethyl-cis-crotonylurea was taken from a production batch thereof, and was found to contain 6000 p.p.m. of silver. The sample was dissolved in isopropanol, treated with a small amount of phosphoric acid, about .05 of 1% by total weight, treated also with char and filtered while hot. From the cool filtrate there was obtained pure Z-ethyl-cis-crotonylurea containing less than 5 p.p.m. of silver and melting at 192-l93.8 C. A recovery of 86% was realized.

Additional plant batches of crude Z-ethyl-cis-crotonylurea were also examined for silver content and purified by adding 450 ml. of phosphoric acid to 169 pounds of 2-ethyl-cis-crotonylurea representing each batch which had been dissolved in 2380 pounds of isopropanol. After treatment with char and filtration, the cold filtrate was centrifuged to obtain purified Z-ethyl-cis-crotonylurea which was re-examined for its silver content. The results were as follows:

Table A Silver content expressed 111 p.p.m. Example No.

Before treat- After treatment ment 2, 500 less than 5.

EXAMPLE 3 Crude Z-ethyI-cis-crotonylurea was obtained in the laboratory as follows: 180 grams of carbromal and grams of silver oxide contained in 450 cos. of isopropanol was treated with 5 ml. of phosphoric acid and the mixture stirred and refluxed for four hours. The reaction mixture thus obtained was treated with char, filtered while hot, .theclear filtrate cooled and the solid isolatedrby filtration. The Z-ethyl-cis-crotonylurea which was ex: tracted weighed 58.6 grams and melted at 186188 On examination, it was found to contain approximately 50 ppm. of silver.

.To review, briefly, the instant invention relates to a methodof producing the higher melting isomer of Z-ethylcrotonylurea, that is, 2-ethyl-cis-crotonylurea.

The method involves the steps of refluxing a solution of 2-bromo-2-ethylbutyry1urea in isopropanol using silver oxidev as a, catalyst. The reaction mixture is then filtered to obtain crude Z-ethyl-cis-crotonylurea which is redissolved in isopropanol to form a second solution. ,The instantimproved process involves the step of adding phosphoric acid to one of the isopropanol solutions in ,suflicient quantity to permit removal of substantially all re- 4 sidual silver and to recover 2-ethyl-cis-crotonylurea containing less than 5 ppm. of residual silver. The amount of phosphoric acid added to the isopropanol is preferably about 0.05% of the total weight of the solution.

What is claimed is:

In a method of purifying crude Z-ethyl-cis-crotonylurea containing silver as a contaminant by dissolving the crude material in isopropanol, treating the solution with a'cti-' vated carbon, filtering the treated solution and extracting the final product from the filtrate, the improvement which comprises adding to said isopropanol from 0.05 to 0.10% of phosphoric acid, the percentage being by weight, based on the weight of the total composition.

References. Cited in the file of this patent UNITED STATES PATENTS 2,734,08 2 Fancher Feb. 7, 1956 

